title: Acidic biphenyl derivatives: synthesis and biological activity of a new series of potent 5-HT(4) receptor antagonists.
abstract: Serotonin (5-hydroxytryptamine, 5-HT) is an important signaling molecule in the central nervous system (CNS) and in non-neuronal tissues and organs. Serotonin mediates a positive chronotropic and inotropic response through 5-HT4 receptors in the atrium and ventricle of the heart. Recent investigations have revealed increased expression of the 5-HT4(b) isoform in cardiomyocytes of chronic arrhythmic and failing hearts, and that the use of 5-HT4 receptor antagonists may be beneficial for treating these conditions. The 5-HT4 receptor possesses a transmembrane (TM) binding site important for ligand affinity and recognition, as well as a capacity to accommodate bulky ligands. A new series of peripherally-acting 5-HT4 receptor antagonists were prepared by combining the acidic biphenyl group from the class of angiotensin II receptor blockers (ARBs) with the SB207266 (piboserod) scaffold. The new compounds were pharmacologically evaluated and carboxylic acid 21 was identified as a potent and promising 5-HT4 receptor antagonist with moderate affinity for the AT1 receptor. The permeability of carboxylic acid 21 in a Caco-2 assay was low and the corresponding prodrug esters 23a-f were therefore prepared. The pharmacokinetics of methyl ester 20 and n-butyl ester 23c were evaluated in a rat model, revealing incomplete metabolism to carboxylic acid 21. However, methyl ester 20 is a potent 5-HT4 receptor antagonist with binding affinities in the low picomolar range. Methyl ester 20 has promising oral bioavailability and pharmacokinetics and may target 5-HT4 receptors in both CNS and peripheral organs.
authors.affiliation: Drug Discovery Laboratory AS, Oslo Innovation Center, N-0349 Oslo, Norway; Department of Medicinal Chemistry, School of Pharmacy, University of Oslo, PO Box 1068 Blindern, N-0316 Oslo, Norway.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Brudeli
authors.forename: Kjetil Wessel
authors.initials: KW
authors.lastname: Andressen
authors.forename: Lise Román
authors.initials: LR
authors.lastname: Moltzau
authors.forename: Nils Olav
authors.initials: NO
authors.lastname: Nilsen
authors.forename: Finn Olav
authors.initials: FO
authors.lastname: Levy
authors.forename: Jo
authors.initials: J
authors.lastname: Klaveness
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology*; D018938:Caco-2 Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006168:Guinea Pigs; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D044422:Receptors, Serotonin, 5-HT4 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry* / Q000235:genetics; D058828:Serotonin 5-HT4 Receptor Agonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D044422:Receptors, Serotonin, 5-HT4; D011994:Recombinant Proteins; D058828:Serotonin 5-HT4 Receptor Agonists; C010574:biphenyl
keywords: 5-HT(4) antagonist; AT(1) antagonists; Bioavailability; Bulky ligand; Hydrophobic pocket